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The present invention is directed to a novel canine DNA sequence encoding the canine growth hormone secretagogue receptor as well as to the protein encoded by that DNA.
Growth hormone (GH) is an anabolic hormone capable of promoting linear growth, weight gain and whole body nitrogen retention in mammals. GH is thought to be released primarily from the somatotroph cells of the anterior pituitary. under the coordinate regulation of two hypothalamic hormones, growth hormone releasing factor (GHRF or GRF) and somatostatin. Both GHRF stimulation and somatostatin inhibition of the release of GH occurs by the specific engagement of receptors on the cell membrane of the somatotroph.
GH release is also stimulated by a group of short peptides known as growth hormone releasing peptides (GHRPs) or as growth hormone secretagogues. Among the GHRPs are GHRP-2 (hexarelin) and GHRP-6, which are described, for example, in U.S. Pat. No. 4,411,890, PCT Patent Pub. No. WO 89/07110, PCT Patent Pub. No. WO 89/07111, PCT Patent Pub. No. WO 93/04081, and J. Endocrinol Invest., 15 (Suppl 4), 45 (1992). GHRPs function by selectively binding to distinct somatotroph cell membrane receptor(s), the growth hormone secretagogue receptor(s) (GHSRs). A medicinal chemical approach has resulted in the design of several classes of orally-active, low molecular weight, non-peptidyl compounds which bind specifically to human GHSRs and result in the pulsatile release of GH. Such compounds possessing growth hormone secretagogue activity are disclosed, for example, in the following: U.S. Pat. No. 3,239,345; U.S. Pat. No. 4,036,979; U.S. Pat. No. 4,411,890; U.S. Pat. No. 5,206,235; and U.S. Pat. No. 5,283,241.
The use of orally-active agents which engage GHSRs and thus stimulate the pulsatile release of GH has been a significant advance in the treatment of growth hormone deficiency in children and adults and provides substantial benefit under circumstances where the anabolic effects of GH can be exploited clinically (e.g., post-hip fracture rehabilitation, the frail elderly, and in post-operative recovery patients). Other uses for such agents are being discovered from time to time. For example, Copinschi et al. 1997, Neuroendocrinol. 66:278-286 indicates that treatment with the non-peptidyl growth hormone secretagogue MK-677 improves sleep quality.
Provision of GHSRs from non-human species would allow for the development of a new set of agents that could be used as veterinary pharmaceuticals in animal disease states analagous to those described above for humans.
The present invention is directed to a novel canine DNA that encodes the canine growth hormone secretagogue receptor (GHSR). The DNA encoding canine GHSR is substantially free from other nucleic acids and has the nucleotide sequence shown in SEQ.ID.NO.:1. Also provided is a canine GHSR protein encoded by the novel DNA sequence. The canine GHSR protein is substantially free from other proteins and has the amino acid sequence shown in SEQ.ID.NO.:2. Methods of expressing the canine GHSR protein in recombinant systems and of identifying agonists and antagonists of the canine GHSR are provided.